This proposal is directed at extending and improving the methodology for the in vivo incorporation of beta amino acids into proteins. Recent efforts have been directed at the development and characterization of peptide like oligomers as modulators of biological activity. The most well studied of these are the peptoids (N-alkyl-glycine oligomers) and the beta-peptides (oligomers of backbone homologated alpha-amino acids) that exhibit increased stability and resistance to proteases; mixed oligomers of alpha/beta peptide units maintain these interesting properties. The in vivo generation of heterogeneous backbone oligomers would allow powerful biological selections (e.g. phage display) to be applied toward their development as materials and medicinals. Specific aim 1 describes in vitro translation experiments designed to determine the tolerance of both the natural and modified translational apparatus towards a wide range of beta-peptide and peptoid residues. Specific aim 2 describes the use of positive and negative selections to evolve aminoacyl tRNA synthetases (aaRS) capable of specifically charging tRNAs with backbone modified residues. Specific aim 3 details experiments directed at the generation of a inhibitors of an important protein protein interaction implicated in many cancers. Inhibitors of the interaction of the anti-apoptotic protein Bcl-xL will be investigated utilizing peptides consisting of alternating alpha and beta amino acid residues displayed on the surface of bacteriophage.